Interaction of novel oxazoline derivatives of 17(20)E-pregna-5,17(20)-diene with cytochrome P450 17A1

• Published in: Biochemistry (Moscow). Supplement. Series B, Biomedical chemistry Biomedical chemistry, 2015-04, Vol.9 (2), p.114-120
• Main Authors: Stulov, S. V., Dugin, N. O., Zharkova, M. S., Shcherbinin, D. S., Kuzikov, A. V., Shumantseva, V. V., Misharin, A. Yu, Veselovsky, A. V.
• Format: Article
• Language: English
• Subjects: Androgens; Biochemistry; Bioorganic Chemistry; Biosynthesis; Cellular biology; Chemistry; Chemistry and Materials Science; Crystal structure; Enzymes; Medicinal Chemistry; Pharmacology
• ISSN: 1990-7508; 1990-7516
• DOI: 10.1134/S1990750815020134

In order to find novel inhibitors of 17α-hydroxylase-17,20-lyase (cytochrome P450 17A1, CYP17A1), a key enzyme of biosynthesis of androgens, molecular docking of six new oxazoline-containing derivatives 17(20) E -pregna-5,17(20)-diene has been carried out to the active site of the crystal structure of CYP17A1 (pdb 3ruk). Results of this study indicate that: (1) complex formation of docked compounds with CYP17A1 causes their isomerization in energetically less favorable 17(20) Z -isomer; (2) the localization of the steroid moiety of all compounds in the active site is basically the same; (3) the structure of the oxazoline moiety significantly influences its position relative to heme as well as the energy of complex formation; (4) coordination of the nitrogen atom of the oxazoline moiety and the heme iron is only possible in the 17(20) Z -conformation with anti oriented double bonds 17(20), and C=N; (5) the presence of two substituents at C4′ of the oxazoline moiety significantly impairs ligand binding; (6) oxazoline- and benzoxazole-containing derivatives 17(20) E -pregna-5,17(20)-diene can effectively inhibit the catalytic activity CYP17A1 and may be of interest as a basis for the development of new drugs for the treatment of androgen-dependent cancer.